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Title: Variants in angiopoietin-2 (ANGPT2) contribute to variation in nocturnal oxyhaemoglobin saturation level

item WANG, HEMING - Case Western Reserve University (CWRU)
item CADE, BRIAN - Brigham & Women'S Hospital
item CHEN, HAN - Harvard School Of Public Health
item GLEASON, KEVIN - Brigham & Women'S Hospital
item SAXENA, RICHA - Brigham & Women'S Hospital
item FENG, TAO - Case Western Reserve University (CWRU)
item LARKIN, EMMA - Vanderbilt University Medical Center
item VASAN, RAMACHANDRAN - Boston University Medical School
item LIN, HONGHUANG - Boston University Medical School
item PATEL, SANJAY - Brigham & Women'S Hospital
item TRACY, RUSSELL - University Of Vermont
item LIU, YOUNGMEI - Wake Forest School Of Medicine
item GOTTLIEB, DANIEL - Brigham & Women'S Hospital
item BELOW, JENNIFER - University Of Texas Health Science Center
item HANIS, CRAIG - University Of Texas Health Science Center
item PETTY, LAUREN - University Of Texas Health Science Center
item SUNYAEV, SHAMIL - Broad Institute Of Mit/harvard
item FRAZIER-WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC)
item ROTTER, JEROME - Harbor-Ucla Medical Center
item POST, WENDY - Johns Hopkins University
item LIN, XIHONG - Harvard School Of Public Health
item REDLINE, SUSAN - Brigham & Women'S Hospital
item ZHU, XIAOFENG - Case Western Reserve University (CWRU)

Submitted to: Human Molecular Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/19/2016
Publication Date: 12/1/2016
Citation: Wang, H., Cade, B.E., Chen, H., Gleason, K.J., Saxena, R., Feng, T., Larkin, E.K., Vasan, R.S., Lin, H., Patel, S.R., Tracy, R.P., Liu, Y., Gottlieb, D.J., Below, J.E., Hanis, C.L., Petty, L.E., Sunyaev, S.R., Frazier-Wood, A.C., Rotter, J.I., Post, W., Lin, X., Redline, S., Zhu, X. 2016. Variants in angiopoietin-2 (ANGPT2) contribute to variation in nocturnal oxyhaemoglobin saturation level. Human Molecular Genetics. 25(23):5244-5253.

Interpretive Summary: Poor sleep quality is associated with an increased risk of obesity. Poorer oxygen levels in the blood during the night are, in turn, associated with poorer sleep quality. The problem is that we do now know why some people have higher or lower blood oxygen levels overnight. In this study, we examined 6,000 individuals who had their overnight blood oxygen levels measured and looked across their whole genome for variants that associated with overnight oxygen levels. We found two variants in the angiopoietin-2 (ANGPT2) that contributed to the variation of overnight oxygen levels in the blood. This research tells us that if we follow up these findings with functional work, we may have a better idea of how to improve overnight oxygen levels, and so reduce this important obesity risk factor.

Technical Abstract: Genetic determinants of sleep-disordered breathing (SDB), a common set of disorders that contribute to significant cardiovascular and neuropsychiatric morbidity, are not clear. Overnight nocturnal oxygen saturation (SaO2) is a clinically relevant and easily measured indicator of SDB severity but its genetic contribution has never been studied. Our recent study suggests nocturnal SaO2 is heritable. We performed linkage analysis, association analysis and haplotype analysis of average nocturnal oxyhaemoglobin saturation in participants in the Cleveland Family Study (CFS), followed by gene-based association and additional tests in four independent samples. Linkage analysis identified a peak (LOD=4.29) on chromosome 8p23. Follow-up association analysis identified two haplotypes in angiopoietin-2 (ANGPT2) that significantly contributed to the variation of SaO2 (P=8×10-5) and accounted for a portion of the linkage evidence. Gene-based association analysis replicated the association of ANGPT2 and nocturnal SaO2. A rare missense SNP rs200291021 in ANGPT2 was associated with serum angiopoietin-2 level (P=1.29×10-4), which was associated with SaO2 (P=0.002). Our study provides the first evidence for the association of ANGPT2, a gene previously implicated in acute lung injury syndromes, with nocturnal SaO2, suggesting that this gene has a broad range of effects on gas exchange, including influencing oxygenation during sleep.